Abstract Heart failure is a growing medical and social problem. Current medical therapies are insufficient to repair the heart and merely postpone death. Stem cell therapy holds promise to be a therapy that could potentially cure heart failure by replacing dead myocardium and scar tissue with new healthy cardiomyocytes. Until a decade ago the heart was considered to be a post-mitotic organ. New findings however, have suggested the heart has some regenerating capacity. Potentially relevant sources of renewal include bone marrow derived cells, such as mesenchymal stem cells, hematopoietic stem cells or endothelial progenitor cells, stem cells residing in the heart, so called Cardiac Progenitor Cells (CPCs) or mitosis by cardiomyocytes. All of these sources are currently being studied, although there is intense debate over the extent to which the heart is capable of regeneration. Currently used models to study cardiac regeneration rely on myocardial infarction, through the induction of a large scar that lacks blood supply. Cardiac stem cells are then isolated and cultured and injected back into the animal to study their salvaging capacities. In this proposal we will take an in vivo approach to study endogenous levels of regeneration. We will investigate regeneration by carrying out the following aims: (1) To examine endogenous stem cell and CPC activation using a novel method for widespread stochastic cardiomyocyte apoptosis throughout the heart. (2) To determine the importance of c-kit positive (cardiac) stem cells for cardiac regeneration using genetically engineered mice. (3) To determine how important cardiac regeneration is for cardiac function as well as assessment of the extent of cellular renewal through a new genetic mouse model to track newly generated myocytes. The initial part of the research proposal will be carried out in the lab or Dr. Jeffery Molkentin, a world renowned cardiac researcher who studies cardiac hypertrophy, calcium signaling and cell death using genetic mouse models. In this lab, I will generate different mouse models to study cardiac regeneration in vivo that I will use to complete the aims proposed here. Moreover, this will provide me with the opportunity to start my independent research career focused on cardiac regeneration. This proposal will open up the field of cardiac regeneration by allowing the study of factors that can enhance the endogenous levels of cardiac repair. Finally, we will begin to determine the relevance of cardiac regeneration for cardiac function and assess the importance of one specific population of stem cells in the process of cardiac repair.